JP2000037450A - Adhesion preventive material and its manufacture - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an adhesion preventive material excellent in adhesion to living tissue and showing a high water content and high glucose permeability and having biological absorbability and appropriate absorption rate. SOLUTION: A 10% aqueous solution is prepared by dissolving gelatin in water, is flow cast on a glass sheet made water-repellent, and is dried to obtain a film that is about 100 μm thick. Next, a sterilizing ultraviolet lamp is used to irradiate the gelatin film obtained with ultraviolet irradiation of 15 watts at a distance of 60 cm for ten hours to obtain an adhesion preventive material.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an adhesion preventing material for preventing adhesion between living tissues and a method for producing the same.

[0002]

2. Description of the Related Art After surgery, adhesions between living tissues often occur, causing pain and dysfunction. However, adhesions are particularly problematic in the fields of obstetrics and gynecology, gastroenterological surgery, orthopedic surgery and cardiac surgery, and are severe. If so, surgery to remove the adhesions will be required. In addition, due to adhesion, it is often difficult to perform a reoperation for the primary disease. In order to prevent this adhesion, there is a method of isolating a site where an adhesion may occur with a membrane, and some methods are used.

[0003]

The materials currently used for such an adhesion preventing method include an oxidized cellulose film and a mixed film of hyaluronic acid and carboxymethyl cellulose, but their effects are extremely insufficient and limited. It is only used in cases that have failed. The present inventors have conducted various studies on the reason why the adhesion preventing effect of the oxidized cellulose film is insufficient, and found that there are two problems described below. That is, the first problem is that the membrane is not sufficiently fixed to the living body and moves from the initial position.
Therefore, the shielding effect is not exerted at a site where adhesion prevention is required. On the other hand, as a method of securely fixing the film, adhesion with an adhesive or suturing with a suture can be considered, but it is difficult to fix the film by these methods because the strength of the oxidized cellulose film is low. Further, even if the fixation can be performed by such a method, it has been revealed by the present inventors that the fixation treatment itself may cause or promote adhesion. Therefore,
In order to obtain an excellent adhesion-preventing effect, it is necessary that the adhesive can be fixed securely and easily simply by sticking it to a living tissue.
Next, the second problem is that when the oxidized cellulose membrane is inserted into a living body, the form collapses and disappears in a short time, and the shielding effect cannot be maintained for a required period. Therefore, it is necessary that the form can be maintained for a longer period of time than the oxidized cellulose membrane, and it is considered that a material that retains the form for about several days and that is quickly absorbed thereafter is preferable.

Incidentally, an adhesion preventing film made of gelatin cross-linked chemically (formaldehyde) is known as UPJO (UPJO).
HN), which is commercially available as Gel film (registered trademark). However, this membrane has a long decomposition and absorption time in a living body, and is not useful in terms of movement in a living body and foreign substance reaction. .

An object of the present invention is to provide an adhesion preventing material having such a function. In other words, in order to be able to securely and easily fix to the living tissue, it has appropriate adhesiveness to the living body, can be easily attached to the living tissue, and retains its form in the living body for a period of about several days Then, an object of the present invention is to provide an anti-adhesion material that can be rapidly absorbed by a living body. Still another object is to provide a method for producing such an adhesion preventing material.

[0006]

In the present invention, the above object has been achieved by irradiating ultraviolet rays to gelatin to crosslink.

That is, the present invention relates to an anti-adhesion material which has been crosslinked by irradiating ultraviolet rays after gelatin has been formed.

The anti-adhesion material of the present invention is preferably crosslinked by irradiating ultraviolet rays for 5 to 15 hours, and is preferably in the form of a film or sponge.

In the adhesion preventing material of the present invention, the water content is preferably in the range of 85 to 95% by weight, and the glucose diffusion coefficient is preferably in the range of 4 × 10 ^-6 to 1 × 10 ^-5 cm ² / s.

Further, the present invention relates to a method for producing an adhesion preventing material, which comprises subjecting gelatin to a crosslinking treatment by irradiating ultraviolet rays after molding.

In the method for producing an adhesion preventing material according to the present invention, it is preferable to irradiate ultraviolet rays for 5 to 15 hours.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION As the gelatin used in the present invention, commercially available gelatin can be used, but those provided for medical use are better than those supplied for food. Those having a low pyrogen content are particularly preferred.

The molding of gelatin can be carried out by a method known as a method of molding gelatin. For example, when it is desired to form a film, gelatin is dissolved in water or an organic solvent, cast on a flat surface such as a glass plate, and dried to obtain a film-shaped product. Or,
After mixing a pore-forming agent such as an inorganic salt into gelatin, only the pore-forming agent is dissolved or foamed and freeze-dried to obtain a sponge-like molded product. Further, a sponge-like sheet may be formed by combining the above.

When a film-shaped molded product is obtained, the adhesion preventing material is preferably a film having a thickness of 10 to 300 μm. More preferred is a film having a thickness of 50 to 150 μm. If it is too thin, it will break easily, and if it is too thick, it will be hard and difficult to use.

When a sponge-like molded product is obtained, the adhesion preventing material preferably has a thickness of 50 to 500 μm and a pore diameter of 5 μm or less.

Although the obtained molded article is absorbed by the living body when inserted into the living body, it must be absorbed more slowly in order to use it as an adhesion preventing material. In the present invention, gelatin is cross-linked by irradiating the molded product with ultraviolet rays, thereby reducing the rate of decomposition and absorption in a living body (hereinafter, also referred to as “absorption rate”). As shown in FIG. 1 to be described later, the decrease in the absorption rate, that is, the degree of remaining of the molded article in the living body is correlated with the irradiation amount of the ultraviolet ray. Just adjust it.
For example, it is possible to increase the amount of ultraviolet irradiation applied to the molded article to reduce the absorption rate, and to decrease the amount of ultraviolet irradiation to increase the absorption rate.

The amount of ultraviolet radiation is not particularly limited, but it is preferable to irradiate, for example, 15 watts of ultraviolet radiation at a distance of 60 cm for 5 to 15 hours from the viewpoint of absorption and decomposition in vivo. When the irradiation time of the ultraviolet ray is less than 5 hours, the decomposition is too fast and the damaged tissue cannot be sufficiently isolated. Conversely, if the time exceeds 15 hours, the absorption and decomposition in the living body will be delayed, causing a foreign body reaction and causing adhesion.

The anti-adhesion material of the present invention comprising gelatin which has been subjected to the ultraviolet treatment as described above has a water content of 85 to 95% by weight and a glucose diffusion coefficient of 4 × 10 ^-6 to 1 × 10 ^-5 cm.
^It has a property of ² / s.

When the water content exceeds 95% by weight, the decomposition and absorption time is shortened (a fast disappearance reduces the adhesion preventing effect). On the other hand, when the water content is less than 85% by weight, the flexibility is reduced and it is difficult to fit the living tissue, so that the adhesion preventing effect is reduced. In addition, when the water content is low, the decomposition and absorption time becomes long, and when the residence time in the body is long, the foreign body reaction in the living body becomes remarkable, and conversely, the effect of preventing adhesion decreases.

The glucose diffusion coefficient is 1 × 10 ⁻⁵ cm ² /
Beyond s, cell infiltration and permeation of body fluid components increase,
The adhesion prevention effect is reduced. On the other hand, when the glucose diffusion coefficient is less than 4 × 10 ⁻⁶ cm ² / s, nutrient permeation to a living body part for the purpose of preventing adhesion is reduced, and tissue repair is delayed.

For the purpose of crosslinking, heat treatment and the like can be used in addition to ultraviolet irradiation. The heat treatment is preferably performed at a temperature of 120 to 170 ° C.

In order to make the film-like molded article easily adhere to the living body, it is preferable to have excellent flexibility.
By adding glycerin, the flexibility of the molded product can be improved. Glycerin is mixed with gelatin before molding and molded. The amount of glycerin to be added is suitably up to about 50% by weight based on gelatin.

[0023]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
In the following examples, “parts” are “parts by weight”, and “%” other than the adhesion occurrence rate is “% by weight”.

Example 1 Gelatin (G from Nitta Gelatin)
0545P) was dissolved in water to prepare a 10% aqueous solution, which was cast on a water-repellent glass plate and dried to obtain a film having a thickness of about 100 μm. Using a UV lamp for sterilization (GL-15, manufactured by Toshiba Corp.), the obtained gelatin film was irradiated with 15 watts of ultraviolet light at a distance of 60 cm for 10, 20, and 40 hours (the front and back sides were halved). Each time), and the following evaluation of the adhesion preventing effect was used. As a comparative product, a commercially available anti-adhesion material was similarly evaluated. Got Lum.

Under anesthesia, the abdomen of a 7-week-old Wistar rat was shaved, the abdomen was disinfected, and the skin and muscle tissue of the abdomen were incised at the midline. The iliac vein inside the abdominal wall was cut and tied with silk to stop bleeding. A 1 × 1.5 cm film sterilized with ethylene oxide gas was attached to the abdominal wall so as to cover the cut portion of the blood vessel and the silk thread, and the abdomen was sutured. One week later, the abdomen was opened, the presence or absence of adhesion was observed, and the adhesion preventing effect was evaluated.
The results are as follows.

<Ultraviolet irradiation time><Adhesion occurrence rate (%)> Control ^{* 1} 890 ^{* 2} 62 10 42 20 77 40 93 Interceed ^{* 3} 70 Seprafilm ^{* 4} 83 * 1: No film is attached. * 2: Attach a film that has not been irradiated with ultraviolet light. * 3: Registered trademark of Ethicon. Woven cloth (knit)
Is attached. * 4: Registered trademark of Genzyme. Paste the film.

As is apparent from the above results, the film irradiated with ultraviolet rays for 10 hours showed the highest adhesion preventing effect. Unless crosslinked by irradiation with ultraviolet rays, the decomposition is too fast and the adhesion preventing effect is low. On the other hand, irradiation with ultraviolet rays for 20 hours or more causes slow decomposition and absorption, inducing a foreign substance reaction and consequently causing adhesion.

Example 2 A 15-watt ultraviolet ray was applied to the gelatin film obtained in Example 1 at a distance of 60 cm from the gelatin film obtained in Example 1 using an ultraviolet lamp for sterilization (GL-15, manufactured by Toshiba Corporation). Irradiation was performed for 10, 20, and 40 hours (the front and back sides were halved for each time) and used for the evaluation of the following bioabsorbable degradation test. The results are as shown in FIG.

The film (1 × 1.5 cm) was sterilized with ethylene oxide gas and subjected to an embedding test as follows. After measuring the dry weight of the film, 7-week-old Wistar
The rats were implanted intraperitoneally. After a certain period of time, the rats were sacrificed and the film was removed from the peritoneal cavity. The excised film was washed lightly and completely dried using a vacuum dryer, and then weighed. The degradability of the gelatin film was measured from the ratio of the initial weight of the film to the residual weight.

As is apparent from FIG. 1, the gelatin film cross-linked by irradiating ultraviolet rays for 10 hours is decomposed in 2 days and absorbed by the living body. It is considered that the effect was exhibited. On the other hand, the gelatin film cross-linked by irradiating with ultraviolet rays for 20 hours or more required two days or more to be decomposed and absorbed, and thus it is considered that a low adhesion preventing effect was exhibited.

As shown in FIG. 1, a gelatin film irradiated with ultraviolet rays for 5 to 15 hours is presumed to have a biodegradation absorption time of about 1 to 7 days, and a high anti-adhesion effect can be expected.

Example 3 A 15-watt ultraviolet ray was applied to the gelatin film obtained in Example 1 at a distance of 60 cm from the gelatin film obtained in Example 1 using an ultraviolet lamp for sterilization (GL-15, manufactured by Toshiba Corporation). Irradiate for 5, 10, 20, 40 hours (half time for front and back), measure water content by the method shown below,
The results are shown in FIG.

The film was treated with a phosphate buffer aqueous solution (PBS)
(−)) Was immersed at 25 ° C. for 2 hours, and further immersed in distilled water at 25 ° C. for 6 hours. The weight of this film was measured and defined as the wet weight. Thereafter, the film was completely dried in a vacuum dryer, weighed, and taken as the dry weight,
The water content was calculated according to the following equation. Water content (%) = [(wet weight−dry weight) / wet weight]
× 100

As is apparent from FIG.
The gelatin film irradiated for 5 hours has a moisture content in the range of 85 to 95%, and when used as an adhesion preventing film, has excellent followability (fit) to living tissue.

Example 4 A 15-watt ultraviolet ray was applied to the gelatin film obtained in Example 1 at a distance of 60 cm from the gelatin film obtained in Example 1 using an ultraviolet lamp for sterilization (GL-15, manufactured by Toshiba Corporation). Irradiation was performed for 10, 20, and 40 hours (the front and back sides were halved for each time), and the glucose permeability was measured by the method described below. The results are shown in FIG.

The film was treated with a phosphate buffer aqueous solution (PBS)
After immersion in (−)) at 20 ° C. for 2 hours, glucose permeability was evaluated using a two-chamber diffusion cell as follows. The hydrated film was sandwiched between polyester meshes and inserted between a donor chamber and a receptor chamber. 5 ml of a PBS (-) solution of glucose adjusted to 10 mg / ml was placed in the donor chamber, and 5 ml of a PBS (-) solution was placed in the receptor chamber. While stirring both chambers at a constant speed at 37 ° C., 20 μl was sampled from the receptor chamber over time, and the glucose concentration was measured using Glucose B-Test Wako (Wako Pure Chemical Industries, Ltd.). The diffusion coefficient of a gelatin film obeys the following Fick's law. ln (1-2C _B / C ₀ ) = (− 2AD / LV) × t

[0037] Here, C _B represents the glucose concentration in the receptor chamber after t seconds (mg / ml). C ₀
Indicates the initial concentration (mg / ml) of the donor chamber.
A is the area of the gelatin film facing the diffusion holes (cm ² )
, D represents the diffusion coefficient of glucose (cm ² / sec), L represents the thickness of the gelatin film (cm), and V represents the volume (ml) of the aqueous solution in the chamber.

The slope was read from a graph in which ln (1-2C _B / C ₀ ) was plotted with respect to time t, and the diffusion coefficient D was calculated.

As is clear from FIG. 3, the gelatin film irradiated with ultraviolet rays for 5 to 15 hours shows preferable glucose permeability.

[0040]

The anti-adhesion material of the present invention exhibits high moisture content and glucose permeability in addition to good adhesion to living tissue,
It is also bioabsorbable and has a moderate absorption rate.

[Brief description of the drawings]

FIG. 1 is a graph showing the results of a bioabsorption degradability test of various gelatin films in which the ultraviolet irradiation time was changed in Example 2.

FIG. 2 is a graph showing the water content of a gelatin film obtained by changing the ultraviolet irradiation time in Example 3.

FIG. 3 is a graph showing the glucose permeability of a gelatin film obtained by changing the ultraviolet irradiation time in Example 4.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Shojiro Matsuda 1 Ishishinmachi Ishiburo, Ayabe-shi, Kyoto Gunze Co., Ltd. Kyoto Research Institute (72) Inventor Hiroo Iwata 1-5-5 Wakayamadai, Shimamotocho, Mishima-gun, Osaka Address 8-203 (72) Inventor Yoshito Raft 2-182 Gokasho Hirookadani, Uji City, Kyoto Prefecture F-term (reference) 4C081 AC03 BA16 BB01 BB04 CB041 CC06 CD151 CE11 DA02 EA03 EA05

Claims (8)

[Claims] An anti-adhesion material which has been cross-linked by further irradiating ultraviolet rays after forming gelatin. 2. The method according to claim 1, wherein the ultraviolet light is irradiated for 5 to 15 hours.
3. The adhesion preventing material according to 1. 3. The method according to claim 1, wherein the form is a film.
3. The adhesion preventing material according to 1. 4. The anti-adhesion material according to claim 1, wherein the anti-adhesion material is in the form of a sponge. 5. The adhesion preventing material according to claim 1, which has a water content of 85 to 95% by weight. 6. A glucose diffusion coefficient of 4 × 10 ^-6 to 1 ×.
The adhesion preventing material according to any one of claims 1 to 5, wherein the adhesion preventing material is 10 ^-5 cm ² / s. 7. A method for producing an adhesion preventing material, which comprises subjecting gelatin to a crosslinking treatment by irradiation with ultraviolet light after molding the gelatin. 8. Irradiation with ultraviolet rays for 5 to 15 hours.
3. The method for producing an adhesion preventing material according to item 1.